This application will examine the in vivo actions of a newly described putative dopaminotrophic (DA) factor, glial cell-derived neurotrophic factor (GDNF) in rats. The proposal will test the hypotheses that GDNF is a specific trophic factor for developing, mature and aged midbrain DA neurons, that GDNF will support human as well as rat DA circuits, and that GDNF will counteract the deleterious effects of dopaminergic neurotoxins. It is proposed to examine actions of GDNF in grafts of fetal neuroblasts placed in oculo. Effects of neuron age will be determined by comparing GDNF activity in developing, mature and aged DA grafts. Specificity will be determined by comparing GDNF activity in DA-, NE- and 5HT-containing grafts. Target influences will be addressed by examining GDNF activity in DA double grafts with striatal, hippocampal or iris targets. Finally, GDNF activity will be evaluated in xenografts of fetal human DA neuroblasts in oculo. It is also proposed to examine actions of GDNF on dopaminergic pathways in intact rats and mice. GDNF will be administered intracranially in 3-, 18-, and 24-month old rats to study effects of CNS age. Interactions of GDNF with dopaminergic neurotoxins, such as 6OHDA (rats) and MPTP (mice) will be evaluated both with "protection" and with facilitation of regeneration protocols. Target appropriateness will be evaluated in situ. Finally, GDNF will be studied in mature and immature syngeneic and allogeneic intracranial grafts and in immature human xenografts to gain further insight into the utility of this molecule to augment growth, differentiation, maintenance, and survival of DA neurons. Actions of GDNF will be evaluated using behavioral, histochemical and in vivo electrochemical techniques. Neurochemical and electrophysiological protocols will also be utilized.